HIV vaccines are currently being developed that elicit virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses (Letvin, 2002). Studies in nonhuman primates have demonstrated that such vaccines may not be able to confer sterile protection against simian immunodeficiency virus (SIV) or simian human immunodeficiency virus (SHIV) infection, but can confer protection against high levels of viral replication and progression of clinical disease. However, we have recently shown that mutations can accrue in virus in vaccinated and then infected monkeys that allows the virus to escape from recognition by dominant epitope specific CTL (Barouch, et al. 2002, 2003). The emergence of viruses with such mutations is associated with the onset of high levels of viral replication and subsequent death of the monkeys with an AIDS-like illness. If CTL-based HIV vaccines are ultimately to be useful, we must devise strategies that avoid these events. Such strategies can only be developed if we have a better understanding of the structural constraints to compensate for the loss of effective dominant epitope-specific CTL. The studies described in this grant application elucidate the viral and immune events associated with this virus escape phenomenon in SHIV and SIV/rhesus monkey models of AIDS. Specifically, these studies include a definition of the 1. Biochemistry and structure of CTL escape viruses. 2. Biologic properties of CTL escape viruses. A. In vitro replicative capacity. B. In vivo replicative capacity. C. Fitness relative to wild type viruses. 3. Nondominant SHIV epitope-specific CTL populations. A. Breadth and magnitude. B. Functional repertoire. C. TCR repertoire. 4. Nondominant epitope-specific CTL and control of SIV replication. [unreadable] [unreadable]